Derivatives of 3-chloro-1,2-propanediol having antifertility activity

ABSTRACT

1. A COMPOUND OF THE FORMULA   Z-CH2-CL   WHEREIN Z IS A DISUBSTITUTED 1,3-DIOXOLAN-4YL OF FORMULA   2-R1,2-R2-1,3-DIOXOLAN-4-YL-   WHEREIN R1 IS ALKYL HAVING FROM ONE TO EIGHT CARBON ATOMS AND R2 IS ALKYL HAVING FROM FIVE TO EIGHT CARBON ATOMS.

United States Patent O 3,840,560 DERIVATIVES F 3-CHLOR0-1,2-PROPANEDIOLHAVING ANTIFERTILITY ACTIVITY Sumanas Rakhit, Dollard-des-Ormeaux,Quebec, Canada,

assignor to Ayerst, McKenna and Harrison Limited,

Ville St. Laurent, Quebec, Canada No Drawing. Continuation-impart ofabandoned application Ser. No. 17,904, Mar. 9, 1970. This applicationJune 2, 1972, Ser. No. 259,067

Int. Cl. C07d 13/04 US. Cl. 260-340.9 2 Claims ABSTRACT OF THEDISCLOSURE Disclosed herein are compounds of the formula Z-CH Cl inwhich Z represents a disubstituted 1,3-dioxan-4-yl of formula in which Ris an alkyl containing from one to eight carbon atoms and R is an alkylcontaining from five to eight carbon atoms.

The compounds induce sterility and methods for their preparation and useare disclosed.

RELATION TO OTHER APPLICATIONS This application is acontinuation-in-part of co-pending application Ser. No. 17,904, filedMar. 9, 1970, now abandoned.

BACKGROUND OF THE INVENTION This invention relates to new derivatives of3-chloro- 1,2-propanediol and to processes for their preparation.

The compounds of this invention have been found to possess valuablepharmacologic properties. For example, the present compounds, causesterility in male mammals without diminishing libido or spermatogenesis.The combination of these pharmacologic properties with the inherent lowtoxicity of these compounds renders them useful agents for populationcontrol.

SUMMARY OF THE INVENTION The compounds of this invention may berepresented by formula I in which Z represents a disubstituted1,3-dioxolan-4-yl of general formula in which R is alkyl containing fromone to eight carbon atoms and R is alkyl containing from five to eightcarbon atoms; or Z represents a substituted ethylene glycol group offormula 3,840,560 Patented Oct. 8, 1974 DETAILS OF THE INVENTION The newderivatives of 3-chloro-1,2-propanediol of formula I of this inventionhave been found to possess useful pharmacologic properties. Morespecifically it may be demonstrated that the compounds of this inventionare capable of causing sterility in standard pharmacologic tests, suchas those described by K. T. Kirton et al., Fed. Proc. 28, 705 (1969) orby J. A. Coppola, Life Sciences 8, 43 (1969). In such tests it may beshown that the compounds of this invention do not interfere with normallibido, coitus and ejaculation. Furthermore, the compounds of thisinvention are able to effect reversible or permanent sterility dependingupon the dose employed.

Recently, attention has been focused on the ability of3-chloro-l,2-propanediol to cause sterility in male rats and otherspecies, see Kirton and Coppola, both cited above. However, thisproperty has been associated with a variety of toxic eifects, forexample, see S. A. Gunn et al. Proc. Soc. Exptl. Biol. Med, 132, 656(1969).

It is the object of this invention to disclose new derivatives of3-chloro-1,2-propanediol, compounds of formula I, which are able toelicit the capacity of 3-chloro-l,2- propanediol to cause sterilizationin the host recipient by a much wider margin of safety.

More specifically, the compounds of this invention of formula I exhibitsubstantially the same minimum effective dose range on a daily basis, as3-chloro-l,2-propanediol for inducing sterility. At this dosage, areversible sterility is induced by all these compounds, and the hostsubsequently becomes fertile after cessation of the medication. Atdosages five to ten times the minimum effective dose, a permanentsterility results on repeated daily doses. However, in contradistinctionto 3-chloro-1,2-propanediol, the compounds of this invention may beadministered on a prolonged basis at dosages fiveto ten-fold greaterthan their minimum effective dose with a survival rate, whereas3-chloro-1,2-propanediol, induces gross toxic effects and an eventual100% mortality under similar conditions.

For example, both 4-(chloromethyl)-2-methyl-2-pentyl- 1,3-dioxolane (I;in which Z is and 3-chloro-1,2-propanediol induce reversible sterilityin rats at an oral minimum effective dose of 2.5 mg./day/rat when testedin the above standard pharmacologic tests. When the former compound, acompound of this invention, is administered orally to rats at 25mg./day/rat for 20 days, sterility results but no effect is observed onnormal libido, coitus and ejaculation. After the medication is stoppedall animals behave normally and enjoy good health; however,approximately one half of the group remain sterile (ED =25 mg./day/ratfor inducing permanent sterility). On the other hand, when the lattercompound, 3-chloro-1,2-propanediol, is administered to rats at 25mg./day/rat for 20 days under the same conditions, none of the ratssurvive.

The substantially wide margin of safety found for the compounds of thisinvention is even more surprising since a related known compound,4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane, described by C. E. Ballow,Biochem. Preparations, 7, 45 (1960), is even more toxic than 3-chloro-1,2-propanediol.

The much wider margin of safety possessed by the compounds of thisinvention allows them to be used to advantage in the following ways.First, the compounds of this invention may be used as effective agentsfor the control of rodent populations. It is an advantage that largerdoses of the compounds of this invention produce surviving sterile malesstill capable of mating, instead of causing their demise. Consequently,when these sterile males mate, they induce of state of pseudopregnancyin the female making the females unavailable for breeding with the stillfertile male members of the colony.

Secondly, in cases where temporary sterility is desired for the purposeof population control the compounds of this invention may be used with amuch greater assurance of safety due to the lower toxicity of thesecompounds.

When the compounds of this invention are employed as agents to inducesterility in warm-blooded animals, e.g. rats, they may be used alone orin combination with pharmacologically acceptable carriers. Thepreparation of these compounds is determined by the solubility andchemical nature of the compound, chosen route of administration andstandard biological practice. For example, they may be administeredorally in solid form containing such excipients as starch, milk sugar,certain types of clay and so forth. They may also be administered orallyin the form of solutions or they may be injected parenterally. Forparenteral administration they may be used in the form of a sterilesolution containing other solutes, for example, enough saline or glucoseto make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary with the particular host under treatment. Generally, treatment isinitiated with small dosages substantially less than the optimum dose ofthe compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. In general,the compound of this invention are most desirably administered at aconcentration level that will generally afford efi'ective resultswithout causing any harmful or deleterious side effects and preferablyat a level that is in a range of from about 0.1 mg. to about 100 mg. perkilo per day, although as aforementioned variations will occur. However,a dosage level that is in the range of from about 1.0 mg. to about 20mg. per kilo per day is most desirably employed in order to achieveeffective results.

When the compounds of this invention are employed as rodent controlagents they may be placed in a bait in which the active ingredient ispresent in a concentration of 0.01 to 2.0 percent. The bait consists ofan edible carrier preferably a highly palatable food to rodents, and maybe a mixture of corn meal, cracked corn, cereal grains, meat or fishscraps, bread crumbs, pellets of prepared cereals, vegetable oils, fishoils, powdered sugar, molasses, and such condiments as salt and spices.The bait thus prepared is placed in an accessible location in an areafrequented by rodents.

The compounds of this invention of formula I, ZCH -Cl, in which Zrepresents a disubstituted 1,3- dioxolan-4-yl of general formula inwhich R and R are as defined above, may be prepared by treating thecommercially available 3-chloro-1,2-propanediol, described by J. B.Conant and O. R. Quayle, Organic Syntheses, Coll. Vol. I, John Wiley andSons, Inc., New York, N.Y. 1941, p. 294, with a ketone of generalformula, R R C='O, in the presence of an acid catalyst, with or withoutthe use of an inert solvent.

In the preceding reaction, the employment of perchloric acid as the acidcatalyst is both effective and convenient. A reaction time of one hourto 72 hours, preferably 16 to 24 hours, and a reaction temperature of 0to C., preferably 15 to 35 C., are most suitable conditions foraccomplishing this reaction. If it is desirable to use an inert solvent,either dioxane or chloroform may be used as the reaction solvent. Manyof the ketones of general formula R R C=O are commercially available.Methods for preparing and descriptions of these ketones may be found inorganic chemistry textbooks; for example, Rodds Chemistry of CarbonCompounds, Vol. I, part C, 2nd ed., S. Coffey, Ed., Elsevier PublishingCo., Amsterdam, 1965, p p. 66-69.

The compound of this invention of formula I,

in which Z represents a substituted ethylene glycol group of formula maybe prepared by treating the commercially available3-chloro-l,2-propanediol with dihydropyran in the presence of an acidcatalyst, with or without the use of an inert solvent.

In the preceding reaction, the employment of phosphorus oxychloride asthe acid catalyst is both effective and convenient. A reaction time ofone hour to 72 hours, preferably 16 to 24 hours, and a reactiontemperature of 0 to 100 0, preferably 15 to 35 C., are most suitableconditions for accomplishing this reaction. If it is desirable to use aninert solvent for this reaction, benzene, ether or tetrahydrofuran maybe used as the reaction solvent.

The following Examples serve to illustrate further this invention.

EXAMPLE 1 A mixture of 2-heptanone (10.0 g.-), 3-chloro-1,2-propanedioland perchloric acid (0.5 ml.) is allowed to stand at room temperaturefor 16 hours. Anhydrous potassium carbonate (1.0 g.) is added to themixture, which is then subjected to filtration. The filtrate isdistilled under reduced pressure to afiord 4-(chloromethyl)-2-methyl-2-pentyl-1,3-dioxolane, b.p. 78-80/ 10 mm., n.m.r. (CD01 6 3.5 (m, 2H) and0.9 (d, 3H).

The procedure of Example 1 may be followed to prepare the compounds offormula I, listed below in Table I. In each case an equivalent amount ofthe appropriate starting material, a ketone of general formula R R C==O,is used instead of Z-heptanone.

TABLE I Ketone of Formula R R C= Product, compound of Formula I R R(Prefix listed beIow)-1,3-dio xolane C5111] C41102-butyl-4-(ch1oromethyl)-2-pentyl- CdHlIi 04H,2-buty1-4-(ch1oromethy1)-2-hexyl- C7H15 C4Ho2-butyl-4-(chloromethyl)-2-heptyl- C EH11 4H 2-buty1-4-(chloromethyl)2-oetyl- CzHs 0 H 4-(ehloromethyl)-2-ethyl-2-pentyl- 03H, 0511114-(chloromethyl)-2-pentyl-2-propyl- C4H CsHn2-butyl-4-(ehloromethyl)-2-pentyl- Cs u C5111!4-(ehloromethyl)-2,2dipentyl- CaHu C5Hn4-(chloromethyl)-2-hexyl-2-pentyl- 01H C5Hn4-(chloromethyl)-2-heptyl-2-pentyl- CsHn 05H4-(chlorornethyl)-2-ootyl-2-pentyl- CH 0 H4-(chloromethyl)-2-hexyl-2-methyl- OzHa CGHIS4-(chloromethyl)-2-ethyl-2-hexyl- C3H7 CQHII!4-(ehloromethyl)-2-hexyl-2-propyl- C4Hu CuHlS2-butyl-4-(chloromethyl)-2-hexyl- 05H CaHra4-(chloromethyl)-2-hexyl-2-pentyl- Co ia CoHra4-(chloromethyl)-2,2-dihexyl- C7H15 CdHlS-(chloromethyl)-2-heptyl-2-hexyl- 08H" CaHia4-(chloromethyl)-2-hexy1-2-octy1- CH 01H;4-(chloromethyl)-2-heptyl-2-methy1- C2H5 01H4-(chloromethyl)-2-ethyl-2-heptyl- C3H C1114-(chloromethyl)-2-heptyl-2-propyl- C411 01H2-butyl-4-(chloromethyl)-2-hepty1- 05H 01H4-(ch1oromethyl)-2-heptyl-2-pentyl- 05H 01H4-(chloromethyl)-2-heptyl-2-hexyl- 01H C1H154-(chloromethyl)-2,2-diheptyl- CsHu C1H15 4(ehloromethyl)-2-heptyl-2-octyl- CH3 08H"4-(chloromethyl)-2-methyl-2-octyl- 02H; CaHu4(chloromethyl)-2-ethyl-2-octyl- CaH1 08H"4-(chloromethyl)-2-oetyl-2-propyl- 04H 08H"2-butyl-4-(chloromethyD-2-oetyl- 05H CaHn4-(chloromethyl)-2-ootyl-2-peutyl- 06H 05H"4-(ehloromethyl)-2-hexyl-2-oetyl- 0 11 05H"4-(ohloromethyl)-2-heptyI-2-octyla n a n 4-(chloromethyl)-2,2-dioety1-EXAMPLE 37 To a solution of 3-chloro-1,2-propanediol (1.0 g.) in 20 ml.of dry benzene, dihydropyran (1.4 g.) and one drop of phosphorusoxychloride are added. The mixture is allowed to stand at roomtemperature for 16 hours. The mixture is poured into ice water andextracted with ether. The ether extract is washed with water, dried andevaporated to dryness. The resulting residue is subjected tochromatography on silica gel. Elution of the column with 6 20% ethylacetate in benzene yields3-chl0ro-1,2-bis(tetrahydropyran-Z-yloxyl)propane, n.m.r. (CDCl;.;) 64.6 4.8 (two doublets, 2H) and 1.6 (broad singlet, 12 H).

I claim: 1. A compound of the formula Z-CH -Cl wherein Z is adisubstituted 1,3-dioxolan-4-yl of formula wherein R is alkyl havingfrom one to eight carbon atoms and R is alkyl having from five to eightcarbon atoms.

2. 4 (Chloromethyl) 2 methyl 2 pentyl 1,3-dioxolane, as claimed in Claim1.

References Cited UNITED STATES PATENTS 8/ 1966 Bertin, et a1 260--340.9

OTHER REFERENCES DONALD G. DAUS, Primary Examiner J. H. TURNIPSEED,Assistant Examiner US. Cl. X.R.

1. A COMPOUND OF THE FORMULA